KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

Eric Fagerberg; John Attanasio; Christine Dien; Jaiveer Singh; Emily A. Kessler; Leena Abdullah; Jian Shen; Brian G. Hunt; Kelli A. Connolly; Edward De Brouwer; Jiaming He; Nivedita R. Iyer; Jessica Buck; Emily R. Borr; Martina Damo; Gena G. Foster; Josephine R. Giles; Yina H. Huang; John S. Tsang; Smita Krishnaswamy; Weiguo Cui; Nikhil S. Joshi

doi:10.1126/science.adn2337

KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

Eric Fagerberg, John Attanasio, Christine Dien, Jaiveer Singh, Emily A. Kessler, Leena Abdullah, Jian Shen, Brian G. Hunt, Kelli A. Connolly, Edward De Brouwer, Jiaming He, Nivedita R. Iyer, Jessica Buck, Emily R. Borr, Martina Damo, Gena G. Foster, Josephine R. Giles, Yina H. Huang, John S. Tsang, Smita KrishnaswamyWeiguo Cui, Nikhil S. Joshi^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

Original language	English (US)
Article number	eadn2337
Journal	Science
Volume	387
Issue number	6735
DOIs	https://doi.org/10.1126/science.adn2337
State	Published - Feb 14 2025

Funding

We thank Joshi lab members for helpful discussions and reviewing the manuscript. We also thank the Yale Flow Cytometry Core, Yale School of Medicine Comparative Pathology Research Core, and the Yale Center for Genome Analysis. Graphical figures, including the print summary figure, were created with Biorender.com. We thank the Wherry lab for providing an initial stock of LCMV Clone13. We thank S. Karimeddiny and S. Lanahan for useful discussion and input. We thank the entire Joshi lab for thoughtful discussion and feedback related to this study. The Yale Flow Cytometry Core is supported in part by NIH grant P30CA016359 and S10OD026996. This work was supported by T32 AI155387(EF), R01CA237037-01A1, grants from the Lung Cancer Research Foundation, and the Pershing Square Sohn Foundation. N.S.J. was supported by Mark Foundation Emerging Leader Award. G.G.F. was supported by Immunohematology/Transfusion Medicine Research Training Award, T32, NHLBI, NIH. B.G.H. was supported by T32AR007016. J.S.T. was supported by Chan Zuckerberg Biohub Investigator Award and NIH (R01AI170116).

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Fagerberg, E., Attanasio, J., Dien, C., Singh, J., Kessler, E. A., Abdullah, L., Shen, J., Hunt, B. G., Connolly, K. A., De Brouwer, E., He, J., Iyer, N. R., Buck, J., Borr, E. R., Damo, M., Foster, G. G., Giles, J. R., Huang, Y. H., Tsang, J. S., ... Joshi, N. S. (2025). KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science, 387(6735), Article eadn2337. https://doi.org/10.1126/science.adn2337

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title = "KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection",

abstract = "Na{\"i}ve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of \textasciitilde{}40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.",

author = "Eric Fagerberg and John Attanasio and Christine Dien and Jaiveer Singh and Kessler, \{Emily A.\} and Leena Abdullah and Jian Shen and Hunt, \{Brian G.\} and Connolly, \{Kelli A.\} and \{De Brouwer\}, Edward and Jiaming He and Iyer, \{Nivedita R.\} and Jessica Buck and Borr, \{Emily R.\} and Martina Damo and Foster, \{Gena G.\} and Giles, \{Josephine R.\} and Huang, \{Yina H.\} and Tsang, \{John S.\} and Smita Krishnaswamy and Weiguo Cui and Joshi, \{Nikhil S.\}",

year = "2025",

month = feb,

day = "14",

doi = "10.1126/science.adn2337",

language = "English (US)",

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Fagerberg, E, Attanasio, J, Dien, C, Singh, J, Kessler, EA, Abdullah, L, Shen, J, Hunt, BG, Connolly, KA, De Brouwer, E, He, J, Iyer, NR, Buck, J, Borr, ER, Damo, M, Foster, GG, Giles, JR, Huang, YH, Tsang, JS, Krishnaswamy, S, Cui, W & Joshi, NS 2025, 'KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection', Science, vol. 387, no. 6735, eadn2337. https://doi.org/10.1126/science.adn2337

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T1 - KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

AU - Fagerberg, Eric

AU - Attanasio, John

AU - Dien, Christine

AU - Singh, Jaiveer

AU - Kessler, Emily A.

AU - Abdullah, Leena

AU - Shen, Jian

AU - Hunt, Brian G.

AU - Connolly, Kelli A.

AU - De Brouwer, Edward

AU - He, Jiaming

AU - Iyer, Nivedita R.

AU - Buck, Jessica

AU - Borr, Emily R.

AU - Damo, Martina

AU - Foster, Gena G.

AU - Giles, Josephine R.

AU - Huang, Yina H.

AU - Tsang, John S.

AU - Krishnaswamy, Smita

AU - Cui, Weiguo

AU - Joshi, Nikhil S.

PY - 2025/2/14

Y1 - 2025/2/14

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AB - Naïve CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9–based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.

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KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

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